Tobacco addiction is a chronic relapsing disorder that is characterized by compulsive tobacco smoking behavior and a negative affective state upon the discontinuation of tobacco use. Smoking has been associated with cancers in nearly all organs and it has been estimated that it leads to the death of 440,000 Americans each year. Research in our laboratory has provided evidence for an important role of the stress neuropeptide corticotropin-releasing factor (CRF) in the negative affective state of nicotine withdrawal. In addition, preliminary studies suggest that stress-induced relapse to nicotine seeking behavior is at least partly mediated by an increased activation of brain CRF and norepinephrine systems. The overall hypothesis guiding the proposed studies is that the negative affective aspects of nicotine withdrawal and stress-induced relapse to nicotine seeking behavior are mediated by a dysregulation of CRF and norepinephrine transmission in brain areas that play a critical role in the regulation of emotional states. The aim of our studies is to identify brain sites that mediate the affective aspects of nicotine withdrawal and contribute to relapse to nicotine seeking behavior. The proposed studies will focus on the role of CRF and norepinephrine in the extended amygdala (central nucleus of the amygdala [CeA] and bed nucleus of the stria terminalis [BNST]) as evidence indicates that an increased release of CRF and norepinephrine in these brain sites contributes to negative mood states and relapse. Specific Aim 1 will explore the role of CRF1, CRF2, a2-adrenergic, and 1/2- adrenergic receptors in the CeA and BNST in the dysphoria associated with nicotine withdrawal. The rat intracranial self-stimulation paradigm will be used to assess the dysphoria associated with nicotine withdrawal. Nicotine withdrawal in rats is associated with elevations in brain reward thresholds (i.e., deficit in brain reward function) that are analogous to the dysphoria experienced by smokers upon a cessation attempt. Specific Aim 2 will explore the role of CRF1, CRF2, a2-adrenergic, and 1/2- adrenergic receptors in the CeA and BNST in stress-induced relapse to nicotine seeking behavior. The proposed studies will provide important information about the role of CRF and norepinephrine in the negative affective state of nicotine withdrawal and in relapse to nicotine seeking behavior. These studies may contribute to the development of novel and improved pharmacotherapies for tobacco addiction. PUBLIC HEALTH RELEVANCE: Tobacco addiction is a chronic disease that is characterized by withdrawal and relapse after periods of abstinence. The proposed experiments focus on the development of novel and non-addictive treatments for the negative mood state associated with nicotine withdrawal and relapse to tobacco smoking. These novel treatments may aid in improving smoking cessation rates.